Title:Molecular
Mechanisms of Development and Reversal of
Alcohol-Induced Liver Fibrosis (R01)

Announcement TypeNew

Update: The following update relating to this announcement has been issued:

August 16, 2010 - IMPORTANT NOTE! NIH has eliminated the error correction window for due dates of January 25, 2011 and beyond. As of January 25, all corrections
must be complete by the due date for an application to be considered on-time. See NOT-OD-10-123.

December 2, 2009 -
This FOA has been updated to reflect the new requirements from NIH’s Enhancing Peer Review Initiative. The new requirements are effective for submissions intended for due dates January 25, 2010 and beyond. If submitting an application intended for a due date of January 25, 2010 and beyond, follow the guidance below and be sure to use the Adobe-Forms-B version of the application forms and instructions. If applying for a due date before January 25, 2010, follow the guidance in the archived version of this FOA and be sure to use the Adobe-Forms-A version of the application forms and instructions.

NOTICE: Applications submitted in response to this Funding Opportunity
Announcement (FOA) for Federal assistance must be submitted electronically
through Grants.gov (http://www.grants.gov)
using the SF424 Research and Related (R&R) forms and the SF424 (R&R)
Application Guide.

APPLICATIONS MAY NOT
BE SUBMITTED IN PAPER FORMAT.

This FOA must be read
in conjunction with the application guidelines included with this announcement
in Grants.gov/Apply
for Grants (hereafter called Grants.gov/Apply).

A registration process is
necessary before submission and applicants are highly encouraged to start the
process at least four weeks prior to the grant submission date. See Section IV.

Purpose.This Funding Opportunity Announcement (FOA) issued by National
Institute on Alcohol Abuse and Alcoholism, National Institutes of Health,
solicits Research Grant (R01) applications from institutions/organizations
that propose to investigate the underlying molecular mechanisms of the development as well as reversal of alcohol-induced liver fibrosis. Liver fibrosis comprises
excessive deposition of extracellular matrix (ECM) components, especially
collagen, and activation
of hepatic stellate cells (HSCs) is the primary event that triggers the
process of fibrogenesis. Understanding the mechanisms of alcohol-induced liver
fibrosis is important for the development of strategies for prevention and
treatment of this condition. This FOA encourages applicants to test small
molecules that reverse or prevent alcohol-induced liver fibrosis.

Mechanism
of Support. This FOA
will utilize the NIH Research Project Grant (R01) award mechanismand runs in parallel with an FOA of identical
scientific scope, PA-07-361that solicits applications under theR21
mechanism.

Funds Available and
Anticipated Number of Awards. Awards issued under this FOA are contingent upon the
availability of funds and the submission of a sufficient
number of meritorious applications.Because the
nature and scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award will
also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of
the applications received.

Eligible
Project Directors/Principal Investigators (PDs/PIs).Individuals with the skills, knowledge, and
resources necessary to carry out the proposed research are invited to work
with their institution/organization to develop an application for support.
Individuals from underrepresented racial and ethnic groups as well as
individuals with disabilities are always encouraged to apply for NIH
support.

Number
of Applications. Applicants may submit more than one application,
provided each application is scientifically distinct.

Renewals
and Resubmissions. Applications can be renewed by competing for
additional project periods.Applicants may submit a
resubmission application, but such application must include an Introduction
addressing the previous peer review critique (Summary Statement).

Number of
PDs/PIs. More than one PD/PI, or multiple PDs/PIs, may be designated
on the application.

Application
Materials.SeeSection IV.1for application materials.All applications, including resubmission, revision and renewal, submitted for due dates January 25, 2010 and beyond, must utilize the current forms and instructions.

General
Information.For general information on SF424 (R&R) Application
and Electronic Submission, see these Web sites:

The
National Institute on Alcohol Abuse and Alcoholism invites grant applications
that will employ an integrated approach to investigate the underlying molecular
mechanisms of the development as well as reversal of alcohol-induced liver
fibrosis. Liver fibrosis is characterized by excessive deposition of
extracellular matrix (ECM) components, especially collagen, due to increased
matrix production and/or decreased matrix degradation. Activation of hepatic
stellate cells (HSCs) is the primary event that triggers the process of
fibrogenesis. Understanding the underlying molecular mechanisms by which
chronic alcohol consumption leads to the development of liver fibrosis, and the
mechanisms by which liver fibrosis is reversed, is important for the
development of strategies for prevention and treatment of this condition.

A.
Development of Liver Fibrosis: Published studies have identified the following factors as contributors to
the development of alcohol-induced liver fibrosis.

A1. Acetaldehyde:

Acetaldehyde,
an immediate metabolite of ethanol, is primarily produced in hepatocytes and
can diffuse out to activate HSCs in a paracrine manner. Acetaldehyde has been
shown to increase collagen production by cultured rat HSCs in vitro via:1)
increasing the transcription of a1(I)
collagen gene; 2) decreasing the synthesis of matrix metalloproteinases-1, an
enzyme known to degrade type I collagen; and 3) increasing the expression of
other extracellular matrix components, including type III collagen and
fibronectin. Acetaldehyde also up-regulates transforming growth factor beta1
(TGF-1) expression, suggesting that some fibrogenic actions of
acetaldehyde could be indirectly mediated by TGF- 1. Acetaldehyde
increased cell membrane-associated PKC activity of HSCs, whereas PKC inhibitors
blocked acetaldehyde-mediated a1(I) collagen
gene up regulation, suggesting a role of this kinase in transducing the
intracellular signal. However, subsequent steps involved in the signal
transduction pathways are not clear, and the molecular mechanisms whereby
acetaldehyde up-regulates gene transcription for collagen and other matrix
proteins are not well understood.

A2. Oxidative
stress:

Chronic
alcohol ingestion causes oxidative stress in the liver by increasing generation
of superoxide anions, hydrogen peroxide, hydroxyl radicals and lipid
peroxidation products. It also decreases glutathione levels in the liver. These
ROS have been shown to stimulate HSC proliferation and collagen synthesis.
Lipid peroxidation products such as malondialdehyde (MDA), and 4-hydroxynonenal
(4-HNE) have been implicated in hepatic fibrosis due to chronic ethanol administration.
Furthermore, MDA and 4-HNE have been shown to induce gene expression of
procollagen a1(I) and increase collagen
production by several folds in cultured HSCs. Studies are needed to clarify the
role, if any, of lipid peroxidation products in activating quiescent HSC, and
identify the molecular and signal transduction pathways involved in this
process.

A3. Role of
Kupffer cells:

Kupffer
cells have been implicated as mediators of alcoholic liver injury through the
release of free radicals as well as generation of inflammatory and fibrogenic
mediators in response to alcohol and lipopolysaccharide (LPS). Tumor necrosis
factor-alpha (TNF-a) produced by activated Kupffer cells may contribute to
HSC activation by inducing apoptosis of hepatocytes. In addition, Kupffer
cell-derived TGF-1has been implicated in the activation of stellate cells
through a paracrine mechanism. Furthermore, using co-cultures of Kupffer cells
and HSCs, it was demonstrated that the stimulatory effect of Kupffer cells on
HSC collagen I production was mediated through xanthine oxidase, NADPH oxidase,
and CYP2E1, which are known sources of ROS. These results suggest a role of
oxidative stress in Kupffer cell-mediated HSC activation. Further studies are necessary
to understand the relative contribution of Kupffer cell mediators and how this
information can be used to prevent fibrosis.

A4. Lipopolysaccharide
(LPS):

Chronic
ethanol exposure is associated with increased transfer of LPS (endotoxin) from
the intestine to portal vein. Elevated levels of endotoxin in plasma can
activate Kupffer cells leading to release of pro-inflammatory and pro-fibrogenic
cytokines and both of these factors can contribute to fibrosis. Recently,
researchers have discovered that activated human HSCs express LPS-recognizing
receptors such as CD14 and TLR4. Furthermore, LPS was shown to induce
activation of NF-kB and JNK and expression of chemokines and adhesion molecules
in activated human HSCs. In cultured rat HSCs, LPS induced expression of
TNF-a, iNOS, and IL-6, which was initiated by MAPK p38 and mediated by
NF-kB. These results suggest that in addition to playing an indirect role via
Kupffer cell activation, LPS may contribute to hepatic fibrosis directly by
regulating gene expression of inflammatory mediators in HSCs. How do these
inflammatory mediators activate HSCs and increase collagen production is not
clear.

A5. Role of
hepatocyte apoptosis:

Hepatocyte
apoptosis is significantly increased in patients with alcoholic hepatitis, and
correlates with disease severity and hepatic fibrosis. Increased apoptosis of
hepatocytes results in increased fibrosis in experimental models. Hepatocyte
apoptosis produces chemokines and inflammation, which in turn may activate
HSCs. Furthermore, apoptosis of hepatocytes results in generation of apoptotic
bodies which can release lipid signals for uptake by Kupffer cells and HSCs.
Phagocytosis of the apoptotic bodies by HSCs and Kupffer cells enhances their
expression of pro-fibrogenic genes, such as TGF-1, that may initiate HSC
activation. These studies suggest that alcohol-induced apoptosis of hepatocytes
may be a mechanism of liver fibrosis. Further studies are required to clarify
the mechanisms by which alcohol ingestion induces the formation of apoptotic
bodies and how these bodies activate HSCs.

A6. Transforming
growth factor-beta1 (TGF-b1):

TGF-b1 is a potent profibrogenic cytokine involved in
hepatic fibrosis. In the liver, it is expressed in Kupffer cells, sinusoidal
endothelial cells and HSCs. It activates HSCs resulting in their conversion to
myofibroblasts which produce excess of ECM proteins including collagens. TGF-b1 can indirectly enhance collagen production via
increasing the expression of platelet-derived growth factor (PDGF), which is a
potent mitogen for HSC proliferation, and by up-regulating the expression of
connective tissue growth factor (CTGF), a fibrogenic cytokine. In addition,
TGF-b1 can enhance its own production in
HSCs in an autocrine manner. Thus, once TGF-b1
is secreted, it can perpetuate both HSC proliferation and increased matrix
production that can result in fibrosis. Recently researchers have discovered
the inhibitor of differentiation 1 (Id1) gene that appears to be a critical
mediator in the TGF-b1-induced transdifferentiation of
rat HSCs. The possible involvement of TGF-b1
in alcohol-induced liver fibrosis is based on the following information.
Patients with advanced alcoholic liver disease exhibit increased hepatic
expression of TGF-b1 mRNA as well as increased serum
levels of TGF-b1. In addition, Kupffer cells
isolated from chronically ethanol exposed rats secreted TGF-b1 which induced Collagen production in HSCs.
Furthermore, acetaldehyde has been shown to enhance the production of TGF-b1 in cultured HSCs. How to use the available
information on TGF-1 for the treatment of liver fibrosis needs further
research.

A7. Platlet-derived
growth factor (PDGF):

PDGF is the
most potent mitogen for HSCs and is therefore likely to be an important
mediator of the increased proliferation of HSCs during hepatic fibrogenesis in
chronic liver diseases. Upregulation of the PDGF receptorb during the transition of quiescent stellate cell to
activated stellate cells is an early event following liver injury. PDGF
produced from activated HSCs, activated Kupffer cells, and infiltrating
macrophages can stimulate HSC proliferation through PDGF receptorb during liver fibrogenesis. TGF-b1, a fibrogenic cytokine, has been shown to
potentiate PDGF-stimulated cell proliferation via inducing expression of PDGF
receptorb. The role of PDGF in mediating the
fibrogenic effect of chronic ethanol in liver needs investigation.

A8. Connective
tissue growth factor (CTGF):

CTGF is a
profibrogenic molecule which is over-expressed in fibrotic liver. CTGF
expression in cultured HSCs is enhanced following their activation or
stimulation by TGF-b1 which itself is a fibrogenic cytokine.
Exogenous CTGF is capable of promoting adhesion and proliferation of cultured
HSCs as well as collagen production by these cells. In addition, CTGF
contributes to the survival of primary HSCs through activation of NF-kappaB
pathway. Furthermore, CTGF is produced at high levels in hepatocytes during
CYP2E1-mdiated ethanol metabolism. The CTGF produced in hepatocytes may
activate HSCs in a paracrine manner. Taken together, these findings suggest a
role of CTGF in alcohol-induced hepatic fibrosis; however, further research is needed
to establish this connection.

A9. Adenosine:

Adenosine,
a potent endogenous regulator of inflammation and tissue repair, is released in
vitro by HepG2 cells in response to ethanol or methotrexate treatment.
Activation of adenosine A2A receptor promotes stellate cell collagen
production. Adenosine release was increased in the liver in response to carbon
tetrachloride (CCl4) and thioacetamide exposure and this was
associated with the development of liver fibrosis. However,

A2 A receptor deficient mice were protected from development of hepatic fibrosis
following exposure to CCl4 or thioacetamide. Whether adenosine plays
a significant role in mediating alcoholic liver fibrosis remains to be
determined.

A10. Leptin:

Leptin
plays an important role in the development of hepatic fibrosis. It is present
in activated stellate cells but not in quiescent HSCs. Leptin has been shown to
increase a1 (I) collagen mRNA and type I collagen production in human
stellate cell line, LX-1, and up-regulate a2(I) collagen gene expression in
cultured rat HSCs. This effect of leptin can be mediated through up-regulation
of TGF-1, enhancement of the TGF1 type II receptor, or increased
production of tissue inhibitor of metalloproteinase-1 (TIMP-1) in activated HSCs. The mechanism of
leptin-induced alcoholic hepatic fibrosis is not clear.

A11. Role
of innate immunity :

The liver
immune system has predominant innate immunity (nonspecific immunity)
comprised of Kupffer cells, natural killer (NK) cells and NKT cells, and interferon
alpha (IFN-a) and interferon gamma (IFN-?) cytokines. Increasing
evidence suggests that these innate immune cells and cytokines play important
roles in regulating the development and progression of liver fibrosis: a)
macrophages have been shown to inhibit liver fibrosis through killing HSCs and
enhancing matrix degradation during recovery; b) innate cytokines IFN-a
and IFN-? inhibit liver fibrosis by blocking TGF-1 signaling and HSC
activation; c) IFN-a in combination with ribavirin has been shown to
attenuate liver fibrosis in patients infected with hepatitis C virus (HCV); and
d) NK cells have been shown to kill activated HSCs
and attenuate the severity of liver fibrosis. These results suggest that
innate immunity (NK/IFNs) plays an important role in suppression of liver
fibrosis. Activation of the innate immune system (NK/IFNs) during HCV infection
may help to control the progression of hepatic fibrosis.

Alcohol-mediated
suppression of the innate immunity has been reported in both animal experiments
and clinical studies. Chronic alcohol consumption has been shown to decrease NK
cell activity and numbers. Decreased NK activity has also been reported in
human alcoholics. Acute ethanol exposure markedly suppresses IFN-b and IFN-g activation of STAT1 signaling pathways in primary hepatocytes. STAT2 and
protein kinase R, which are the key downstream signaling components for IFN-a, are significantly downregulated in human alcoholic
liver disease. Chronic alcohol consumption interferes with the efficacy of IFN-a treatment in HCV patients. Since these innate immune
cells and cytokines play an important role in suppressing liver fibrosis as
discussed above, alcohol suppression of innate immunity may be a mechanism
whereby alcohol accelerates liver fibrosis in HCV patients. Further research is
required to investigate the role of innate immune system in alcoholic liver
fibrosis.

A12. HCV
and liver fibrosis:

Alcohol
consumption is known to accelerate the process of liver fibrosis in patients
infected with HCV, but the mechanisms of this interaction are not clear.
Alcohol consumption has been shown to increase apoptosis of hepatocytes and
oxidative stress in patients with chronic hepatitis C virus infection.
Furthermore, HCV core protein and chronic alcohol consumption additively
increased lipid peroxidation and synergistically increased hepatic TNF-a
and TGF-1 expression in HCV core protein-expressing transgenic mice. All these fibrogenic factors
apoptosis, oxidative stress, lipid peroxidation, TNF-a, and TGF-1 -
may be involved in promoting the effect of alcohol on hepatic fibrosis in HCV
infected patients. Further research is required to establish the connection
between alcohol, HCV, and liver fibrosis and identify targets for intervention.

B.
Reversion of Liver Fibrosis

Reversion
of fibrosis may be accomplished by inducing apoptosis or necrosis of activated
HSCs, or by transformation of activated HSCs to quiescent phenotype.

B1. Apoptosis
of activated HSCs:

Spontaneous
resolution of experimental fibrosis is associated with the clearance of collagen-producing
a-SMA positive myofibroblasts (activated HSCs and transdifferentiated
portal fibroblasts), which has been attributed to the induction of apoptosis of
these cells. Apoptosis of myofibroblasts is associated with decreased
expression of TIMP mRNA but increased collagenase activity in the liver. This
concept of spontaneous reversion of fibrosis mediated by HSC apoptosis has been
used to design chemical-induced apoptosis of activated HSCs. For example,
gliotoxin induces apoptosis of activated HSC which resulted in the resolution
of liver fibrosis induced by CCl4 in experimental animals . In addition, sulfasalazine has
been shown to induce apoptosis of activated rat and human stellate cells in
vitro, and promote accelerated recovery from CCl4 -induced fibrosis
in rats. This effect was mediated through the inhibition of the inhibitor of
kappaB kinases, blocking the NF-kB pathway. TIMP-1 protects activated HSCs from
apoptosis and blocking TIMP-1 with specific monoclonal antibody reverses CCl4-induced
hepatic fibrosis. Hepatocyte growth factor (HGF)
stimulates hepatocyte regeneration but apoptosis of activated HSCs and reversal
of fibrosis. Further research is required to identify agents that will
selectively cause apoptosis of activated HSCs without adversely affecting hepatocytes.

B2.
Necrosis of activated HSCs:

Activated
HSCs can be selectively killed by the endogenous cannabinoid anandamide via
inducing necrosis. Anandamide blocks HSC proliferation at concentrations of 1
to 10 micromol/L. At higher concentrations (25-100 micromol/L), anandamide
dose-dependently induced cell death in culture-activated and in vivo-activated
HSCs. The cell death was caspase-independent and showed typical features of
necrosis, such as rapid adenosine triphosphate depletion and propidium iodide
uptake. Anandamide induces ROS formation and increased intracellular Ca(2+)
levels. Pretreatment with the antioxidant glutathione or Ca(2+)-chelation
attenuated anandamide-induced cell death. In primary hepatocytes, anandamide
failed to induce cell death even after prolonged treatment. Thus, anandamide
efficiently induces necrosis in activated HSCs, an effect that depends on
membrane cholesterol and a subsequent increase in intracellular Ca(2+) and ROS.
The anti-proliferative effects and the selective killing of HSCs, but not
hepatocytes, indicate that anandamide may be used as a potential
anti-fibrogenic tool. Studies are required to test the efficacy and safety of
anandamide and other related agents in animal models of liver fibrosis.

One
theoretical approach to reverse fibrosis is the reverse trans-differentiation of
activated HSCs to quiescent phenotype. Quiescent HSCs are full of Vitamin A and
triglycerides which are depleted in the activated HSCs. The
adipogenic/lipogenic transcriptional regulation conferred by PPAR?,
LXRa, and SREBP-1c is required for the maintenance of the fat-storing
quiescence phenotype of HSCs. Expression of these adipogenic transcription
factors is lost in activated HSCs. On the other hand, treatment of the
activated HSCs with an adipocyte differentiation cocktail or ectopic expression
of PPAR? or SREBP-1c causes their reversal to the quiescent phenotype. Of
the known adipogenic transcription factors, PPAR? has been investigated
extensively. The expression of PPAR? is reduced in activated HSCs which
can be restored with PPAR? ligands. Furthermore, by using adenoviral
vector to ectopically express PPAR? in culture-activated HSCs, researchers
have demonstrated that expression of PPAR? can restore the morphological
and biochemical characteristics of quiescent HSCs, including accumulation of
vitamin A. These findings suggest a possibility that PPAR? and other
adipogenic factors may serve as important therapeutic targets for liver fibrosis.
Indeed, researchers have demonstrated the therapeutic efficacy of two
thiazolidinedione (TZD) derivatives, the PPAR? ligands pioglitazone and
rosiglitazone in two toxic and one cholestatic models of liver fibrosis. However,
in a recent human study, pioglitazone was found to be ineffective in reducing
liver fibrosis in subjects with nonalcoholic steatohepatitis. Further studies
are required to test the efficacy of PPAR? and other adipogenic factors in
the treatment of liver fibrosis.

Areas of Research:

Examples of
research that might be supported under this PA include, but are not limited to,
the following:

Specifically,
if you are a U.S. organization and are submitting an application with direct
costs in each year of $250,000 or less (excluding consortium Facilities and Administrative
[F&A] costs), use the PHS398 Modular Budget component provided in the SF424
(R&R) Application Package and SF424 (R&R) Application Guide (see
specifically Section 3.4, Modular Budget Component, of the Application
Guide).

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign
applicants must complete and submit budget requests using the Research &
Related Budget component found in the application package for this FOA. See NOT-OD-06-096,
August 23, 2006.

2.
Funds Available

Because the nature and scope
of the proposed research will vary from application to application, it is
anticipated that the size and duration of each award will also vary. Although
the financial plans of the Institutes and Centers (ICs) provide support for
this program, awards pursuant to this funding opportunity are contingent upon
the availability of funds and the submission of a sufficient number of
meritorious applications.

NIH grants policies as described in the NOT-OD-05-004,
November 2, 2004.

Section
III. Eligibility Information

1. Eligible Applicants

1.A. Eligible
Institutions

You may submit an
application(s) if your institution/organization has any of the following
characteristics:

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the PD/PI is invited to work
with his/her organization to develop an application for support. Individuals
from underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH support.

More than one PD/PI, or multiple
PDs/PIs, may be designated on the application for projects that require a team
science approach that clearly does not fit the single-PD/PI
model.Additional information on the implementation plans and policies and
procedures to formally allow more than one PD/PI on individual research
projects is available athttp://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (seehttp://era.nih.gov/ElectronicReceipt/preparing.htmfor instructions).

The decision of whether to apply for a single PD/PI or
multiple PD/PI grant is the responsibility of the investigators and applicant
organizations and should be determined by the scientific goals of the project.
Applications for multiple PD/PI grants will require additional information, as
outlined in the instructions below. When considering multiple
PDs/PIs, please be aware that the structure and governance of the PD/PI leadership
team as well as the knowledge, skills and experience of the individual PD/PIs
will be factored into the assessment of the overall scientific merit of the
application. Multiple PDs/PIs on a project share the authority and
responsibility for leading and directing the project, intellectually and
logistically.Each PD/PI is responsible and accountable to the grantee
organization, or, as appropriate, to a collaborating organization, for the
proper conduct of the project or program, including the submission of required
reports. For further information on multiple PDs/PIs, please seehttp://grants.nih.gov/grants/multi_pi.

Applications can be renewed
by competing for additional project periods.

Applicants may submit
more than one application, provided each application is scientifically distinct.

Section
IV. Application and Submission Information

Registration:
Appropriate registrations with Grants.gov and eRA Commons must be completed on or before the due date in order to successfully submit an application. Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered with both Grants.gov and the Commons. All registrations must be complete by the submission deadline for the application to be considered �on-time� (see 3.C.1 for more information about on-time submission).

The individual(s) designated as
PDs/PIs on the application must also be registered in the NIH eRA Commons.In the case of multiple PDs/PIs, all PDs/PIs must be registered and be assigned
the PI role in the eRA Commons prior to the submission of the application.

Each PD/PI must
hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization
Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if they have both a
PD/PI role and an Internet Assisted Review (IAR) role, both roles should exist
under one Commons account.

When multiple PDs/PIs are
proposed, all PDs/PIs at the applicant organization must be affiliated with
that organization.PDs/PIs located at another institution need not be
affiliated with the applicant organization, but must be affiliated with their
own organization to be able to access the Commons.

This registration/affiliation must
be done by the AOR/SO or their designee who is already registered in the Commons.

Both the PD/PI(s) and
AOR/SO need separate accounts in the NIH eRA Commons since both are authorized
to view the application image.

Note that if a PD/PI is
also an NIH peer-reviewer with an Individual DUNS and CCR registration, that
particular DUNS number and CCR registration are for the individual reviewer
only. These are different than any DUNS number and CCR registration used by an
applicant organization. Individual DUNS and CCR registration should be used
only for the purposes of personal reimbursement and should not be used on any
grant applications submitted to the Federal Government.

Several of the steps of
the registration process could take four weeks or more. Therefore, applicants
should immediately check with their business official to determine whether
their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept
electronic applications only from organizations that have completed all
necessary registrations.

1. Request Application Information

Applicants must
download the SF424 (R&R) application forms and the SF424 (R&R)
Application Guide for this FOA through Grants.gov/Apply.

Note:
Only the forms package directly attached to a specific FOA can be used. You
will not be able to use any other SF424 (R&R) forms (e.g., sample forms,
forms from another FOA), although some of the "Attachment" files may
be useable for more than one FOA.

Prepare all applications
using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

The SF424 (R&R)
Application Guide is critical to submitting a complete and accurate application
to NIH. There are fields within the SF424 (R&R) application components
that, although not marked as mandatory, are required by NIH (e.g., the
Credential log-in field of the Research & Related Senior/Key Person
Profile component must contain the PD/PIs assigned eRA Commons User ID).
Agency-specific instructions for such fields are clearly identified in the
Application Guide. For additional information, see Frequently Asked Questions
Application Guide, Electronic
Submission of Grant Applications.

The SF424 (R&R)
application has several components. Some components are required, others are
optional. The forms package associated with this FOA in Grants.gov/APPLYincludes all applicable components, required and optional. A completed
application in response to this FOA includes the data in the following
components:

Format: Every effort should be made to comply
with the format specifications, which are based upon a standard U.S. paper s ize of 8.5 x 11 within each PDF.

Funds for up to 8% administrative costs
(excluding equipment) may be requested. SeeNOT-OD-01-028, March 29, 2001.

Organizations must comply with Federal/NIH
policies on human subjects, animals, and biohazards.

Organizations must comply with Federal/NIH
biosafety and biosecurity regulations. See Section VI.2., Administrative and National Policy Requirements.

Proposed research should provide special opportunities for
furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not
readily available in the United States or that augment existing U.S. resources.

SPECIAL
INSTRUCTIONS

Applications with
Multiple PDs/PIs

When multiple PDs/PIs
are proposed, NIH requires one PD/PI to be designated as the "Contact PI,
who will be responsible for all communication between the PDs/PIs and the NIH,
for assembling the application materials outlined below, and for coordinating
progress reports for the project. The contact PD/PI must meet all eligibility
requirements for PD/PI status in the same way as other PDs/PIs, but has no
other special roles or responsibilities within the project team beyond those
mentioned above.

Information for the
Contact PD/PI should be entered in Item 13 of the SF424 (R&R) Cover
component.All other PDs/PIs should be listed in the Research &
Related Senior/Key Person component and assigned the project role of
PD/PI.Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission.The Commons ID of each PD/PI must be included
in the Credential field of the Research & Related Senior/Key Person
component.Failure to include this data field will cause the application
to be rejected.

All projects proposing Multiple PDs/PIs will
be required to include a new section describing the leadership of the project.

Multiple PD/PI Leadership Plan: For applications designating
multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI
Leadership Plan, must be included.
A rationale for choosing a multiple PD/PI approach should be described. The
governance and organizational structure of the leadership team and the research
project should be described, including communication plans, process for making
decisions on scientific direction, and procedures for resolving
conflicts.The roles and administrative, technical, and scientific
responsibilities for the project or program should be delineated for the
PDs/PIs and other collaborators.

If budget allocation
is planned, the distribution of resources to specific components of the project
or the individual PDs/PIs should be delineated in the Leadership Plan. In the
event of an award, the requested allocations may be reflected in a footnote on
the Notice of Award.

Applications
Involving a Single Institution

When all PDs/PIs are
within a single institution, follow the instructions contained in the SF424
(R&R) Application Guide.

Applications
Involving Multiple Institutions

When multiple institutions
are involved, one institution must be designated as the prime institution and
funding for the other institution(s) must be requested via a subcontract to be
administered by the prime institution. When submitting a detailed budget, the
prime institution should submit its budget using the Research & Related
Budget component.All other institutions should have their individual
budgets attached separately to the Research & Related Subaward Budget
Attachment(s) Form.See Section 4.8 of the SF424 (R&R) Application
Guide for further instruction regarding the use of the subaward budget
form.

When submitting a
modular budget, the prime institution completes the PHS398 Modular Budget
component only.Information concerning the consortium/subcontract budget is
provided in the budget justification. Separate budgets for each
consortium/subcontract grantee are note required when using the Modular budget
format. See Section 3.4 of the Application Guide for further instruction
regarding the use of the PHS398 Modular Budget component.

Applications may be submitted on or after the opening date and must be successfully
received by Grants.gov no later than 5:00 p.m. local
time(of the applicant
institution/organization) on the application due date(s). (See Section
IV.3.A. for
all dates.) If
an application is not submitted by the due date(s) and time, the application
may be delayed in the review process or not reviewed. All applications must meet the following criteria to be considered on-time:

All registrations must be complete prior to the submission deadline

The application must receive a Grants.gov tracking number and timestamp (or eRA help desk ticket confirming a system issue preventing submission) by 5:00 p.m. local time on the submission deadline date.

Any system identified errors/warnings must be corrected and the submission process completed within the error correction window.

Submission to Grants.gov is not the last step - applicants must follow their application through to the eRA Commons to check for errors and warnings and view their assembled application!

3.C.2 Two Day Window to Correct eRA Identified Errors/Warnings

IMPORTANT NOTE! NIH has eliminated the error correction window for due dates of January 25, 2011 and beyond.
As of January 25, all corrections must be complete by the due date for an application to be considered on-time. See
NOT-OD-10-123.

Once an application
package has been successfully submitted through Grants.gov NIH provides applicants a two day error correction window to correct any eRA identified errors or warnings before a final assembled application is created in the eRA Commons. The standard error correction window is two (2) business days, beginning the day after the submission deadline and excluding weekends and standard federal holidays. All errors must be corrected to successfully complete the submission process. Warnings will not prevent the application from completing the submission process.

Note that the following caveats apply:

Initial application submission must be on-time.

The AOR/institutions is expected to enforce that application changes made within the error correction window are restricted to those necessary to address system-identified errors/warnings. NIH may reject any application that includes additional changes.

Proof of on-time submission (e.g., Grants.gov timestamp and tracking number) and description of all changes made within the window must be documented in the PHS 398 Cover Letter component of the application.

3.C.3 Viewing an Application in the eRA Commons

Once any eRA identified errors have been addressed and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two weekdays (Monday Friday, excluding Federal holidays) to view the assembled application before it automatically moves forward to NIH for further processing.

If
everything is acceptable, no further action is necessary. The application will
automatically move forward for processing by the Division of Receipt and
Referral, Center for Scientific Review, NIH, after two business days, excluding
Federal holidays.

Prior
to the submission deadline, the AOR/SO can Reject the assembled application
and submit a changed/corrected application within the two-day viewing window.
This option should be used if the AOR/SO determines that warnings should be
addressed or if information was lost or compromised during transmission.
Reminder: warnings do not stop further application processing. If an
application submission results in warnings (but no errors), it will
automatically move forward after two business days if no action is taken.
Please remember that some warnings may not be applicable or may need to be
addressed after application submission.

If
the two-day window falls after the submission deadline, the AOR/SO will have the option to Reject the application if, due to an eRA Commons or Grants.gov
system issue, the application does not correctly reflect the submitted
application package (e.g., some part of the application was lost or did not
transfer correctly during the submission process). The AOR/SO should first
contact the eRA Commons Helpdesk to confirm the system error,
document the issue, and determine the best course of action. NIH will not
penalize the applicant for an eRA Commons or Grants.gov system issue.

If
the AOR/SO chooses to Reject the image after the submission deadline for a
reason other than an eRA Commons or Grants.gov system failure, a
changed/corrected application still can be submitted, but it will be subject to
the NIH late policy guidelines and may not be accepted. The reason for
this delay should be explained in the cover letter attachment.

Both
the AOR/SO and PD/PI will receive e-mail notifications when the application is
rejected or the application automatically moves forward in the process after
two days.

Upon
receipt, applications will be evaluated for completeness by the Center for
Scientific Review, NIH. Incomplete applications will not be reviewed.

There will
be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR receives
the Grants.gov acknowledgments. The AOR and the PI receive Commons
acknowledgments. Information related to the assignment of an application to a
Scientific Review Group is also in the Commons.

Note: Since email can be unreliable, it is the
responsibility of the applicant to check periodically on their application
status in the Commons.

The
NIH will not accept any application in response to this FOA that is essentially
the same as one currently pending initial merit review unless the applicant
withdraws the pending application. The NIH will not accept any application that
is essentially the same as one already reviewed. This does not preclude the
submission of an application already reviewed with substantial changes, but
such application must include an Introduction addressing the previous
critique. Note such an application is considered a "resubmission" for
the SF424 (R&R).

All NIH awards are
subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants
Policy Statement.

Pre-award costs are
allowable. A grantee may, at its own risk and without NIH prior approval, incur
obligations and expenditures to cover costs up to 90 days before the beginning
date of the initial budget period of a new or competing renewal (formerly
competing continuation) award if such costs: are necessary to conduct the
project, and would be allowable under the grant, if awarded, without NIH prior
approval. If specific expenditures would otherwise require prior approval, the
grantee must obtain NIH approval before incurring the cost. NIH prior approval
is required for any costs to be incurred more than 90 days before the beginning
date of the initial budget period of a new or competing renewal award.

The incurrence of pre-award costs in
anticipation of a competing or non-competing award imposes no obligation on NIH
either to make the award or to increase the amount of the approved budget if an
award is made for less than the amount anticipated and is inadequate to cover
the pre-award costs incurred. NIH expects the grantee to be fully aware that
pre-award costs result in borrowing against future support and that such
borrowing must not impair the grantee's ability to accomplish the project
objectives in the approved time frame or in any way adversely affect the
conduct of the project. See the NIH Grants
Policy Statement.

6. Other Submission
Requirements

PD/PI Credential (e.g., Agency Login)

The
NIH requires the PD/PI(s) to fill in his/her Commons User ID in the PROFILE
Project Director/Principal Investigator section, Credential log-in field of
the Research & Related Senior/Key Person Profile component.

Organizational DUNS

The
applicant organization must include its DUNS number in its Organization Profile
in the eRA Commons. This DUNS number must match the DUNS number provided at CCR
registration with Grants.gov. For
additional information, see Frequently Asked Questions Application Guide, Electronic
Submission of Grant Applications.

PHS398 Research Plan Component Sections

Item 3 of the PHS398 Research Plan is limited to 12 pages.

All
application instructions outlined in the SF424 (R&R) Application Guide are
to be followed, incorporating "Just-in-Time" information concepts,
and with the following additional requirements:

R01
applications from U.S. institutions/organizations requesting up to $250,000 per
year in direct costs (excluding consortium F&A costs) must be submitted in
a modular budget format. Additional information on modular budgets is available
at http://grants.nih.gov/grants/funding/modular/modular.htm.When
submitting a modular budget, the applicant organization will include only the
PHS398 Modular Budget component.See Section 3.4 of the SF424 (R&R) Application Guide for further
instructions regarding the use of the PHS398 Modular Budget component.

Foreign organizations
may not submit modular budgets. See NOT-OD-06-096.

Special Instructions for Applications Requesting
$500,000 (direct costs) or More Per Year

Applicants
requesting $500,000 or more in direct costs for any year (excluding consortium
F&A costs) must carry out the following steps:

1) Contact the
IC program staff at least 6 weeks before submitting the application, i.e., as
you are developing plans for the study;

2)
Obtain agreement from the IC staff that the IC will accept your application for
consideration for award; and,

3)
Include the PHS398 Cover Letter component with the application to identify the
staff member and IC who agreed to accept assignment of the application.

NIH has published new limitations on grant application
appendix materials to encourage applications to be as concise as possible while
containing the information needed for expert scientific review. See
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html.

Do not use the Appendix to circumvent the page limitations. An application that does not observe the required page limitations
may be delayed in the review process.

Foreign Applications (Non-domestic (non-U.S.) Entity)

Indicate how the proposed project has specific
relevance to the mission and objectives of the IC and has the potential
for significantly advancing the health sciences in the United States.

Plan for Sharing Research Data

The
precise content of the data-sharing plan will vary, depending on the data being
collected and how the investigator is planning to share the data. Applicants
who are planning to share data may wish to describe briefly the expected
schedule for data sharing, the format of the final dataset, the documentation
to be provided, whether or not any analytic tools also will be provided,
whether or not a data-sharing agreement will be required and, if so, a brief
description of such an agreement (including the criteria for deciding who can
receive the data and whether or not any conditions will be placed on their
use), and the mode of data sharing (e.g., under their own auspices by mailing a
disk or posting data on their institutional or personal Web site, through a
data archive or enclave). Investigators choosing to share under their own
auspices may wish to enter into a data-sharing agreement. References to data
sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their
application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing.
All investigators responding to this funding opportunity should include a
description of how final research data will be shared, or explain why data
sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing
research data will be assessed by the reviewers. However, reviewers will not
factor the proposed data sharing plan into the determination of scientific
merit or the impact/priority score.

Sharing
Research Resources

NIH
policy expects that grant awardee recipients make unique research resources
readily available for research purposes to qualified individuals within the
scientific community after publication (See the NIH Grants Policy Statementhttp://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a sharing
research resources plan addressing how unique research resources will be shared
or explain why sharing is not possible.

The adequacy of the resources sharing plan and any
related data sharing plans will be considered by Program staff of the funding
organization when making recommendations about funding applications. The
effectiveness of the resource sharing will be evaluated as part of the
administrative review of each Non-Competing Grant
Progress Report (PHS 2590). See Section VI.3.,
Reporting.

Section V. Application Review Information

1.
Criteria (Update: Enhanced review criteria have been issued for the evaluation of research applications received for potential FY2010 funding and thereafter - see NOT-OD-09-025).

Only the review
criteria described below will be considered in the review process.

2.
Review and Selection Process

Applications
submitted for this funding opportunity will be assigned to the ICs on the basis
of established PHS referral guidelines.

Undergo
a selection process in which only those applications deemed to have the
highest scientific merit, generally the top half of applications under
review, will be discussed and assigned an impact/priority score.

Receive
a written critique.

Receive a
second level of review by the appropriate advisory council or board

Applications
submitted in response to this funding opportunity will compete for available
funds with all other recommended applications. The following will be considered
in making funding decisions:

Scientific
merit of the proposed project as determined by peer review.

Availability
of funds.

Relevance
of program priorities.

The goals of NIH
supported research are to advance our understanding of biological systems, to
improve the control of disease, and to enhance health. In their written
critiques, reviewers will be asked to comment on each of the following criteria
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.

Significance

Investigator

Innovation

Approach

Environment

Note that an application does not need to be strong in
all categories to be judged likely to have major scientific impact and thus
deserve a high impact/priority score. For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

Overall Impact. Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance: Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s): Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation: Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach: Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed??

Environment: Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

2.A.
Additional Review Criteria

As applicable for the project
proposed, reviewers will consider the following additional items in the
determination of scientific and technical merit, but will not give separate
scores for these items.

Protections for Human Subjects. For
research that involves human subjects but does not involve one of the six
categories of research that are exempt under 45 CFR Part 46, the committee will
evaluate the justification for involvement of human subjects and the proposed
protections from research risk relating to their participation according to the
following five review criteria: 1) risk to subjects, 2) adequacy of protection
against risks, 3) potential benefits to the subjects and others, 4) importance
of the knowledge to be gained, and 5) data and safety monitoring for clinical
trials.

For research that involves human subjects and meets
the criteria for one or more of the six categories of research that are exempt
under 45 CFR Part 46, the committee will evaluate: 1) the justification for the
exemption, 2) human subjects involvement and characteristics, and 3) sources of
materials.

Inclusion of Women, Minorities, and Children.
When the proposed project involves clinical research, the committee will
evaluate the proposed plans for inclusion of minorities and members of both
genders, as well as the inclusion of children.

Vertebrate Animals. The committee
will evaluate the involvement of live vertebrate animals as part of the
scientific assessment according to the following five points: 1) proposed use of
the animals, and species, strains, ages, sex, and numbers to be used; 2)
justifications for the use of animals and for the appropriateness of the species
and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting
discomfort, distress, pain and injury to that which is unavoidable in the
conduct of scientifically sound research including the use of analgesic,
anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and
5) methods of euthanasia and reason for selection if not consistent with the
AVMA Guidelines on Euthanasia.

Resubmission Applications. When
reviewing a Resubmission application (formerly called an amended application),
the committee will evaluate the application as now presented, taking into
consideration the responses to comments from the previous scientific review
group and changes made to the project.

Renewal Applications. When reviewing
a Renewal application (formerly called a competing continuation application),
the committee will consider the progress made in the last funding period.

Revision Applications. When
reviewing a Revision application (formerly called a competing supplement
application), the committee will consider the appropriateness of the proposed
expansion of the scope of the project. If the Revision application relates to a
specific line of investigation presented in the original application that was
not recommended for approval by the committee, then the committee will consider
whether the responses to comments from the previous scientific review group are
adequate and whether substantial changes are clearly evident.

Biohazards. Reviewers will assess
whether materials or procedures proposed are potentially hazardous to research
personnel and/or the environment, and if needed, determine whether adequate
protection is proposed.

Additional Review Considerations

As applicable for the
project proposed, reviewers will address each of the following items, but will
not give scores for these items and should not consider them in providing an
overall impact score.

Budget and Period Support. Reviewers
will consider whether the budget and the requested period of support are fully
justified and reasonable in relation to the proposed research.

Select Agents Research. Reviewers
will assess the information provided in this section of the application,
including 1) the Select Agent(s) to be used in the proposed research, 2) the
registration status of all entities where Select Agent(s) will be used, 3) the
procedures that will be used to monitor possession use and transfer of Select
Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security
of the Select Agent(s).

Applications from Foreign Organizations.
Reviewers will assess whether the project presents special opportunities for
furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions that exist in other countries and
either are not readily available in the United States or augment existing U.S.
resources.

A formal notification in the form of a Notice of Award
(NoA) will be provided to the applicant organization. The NoA signed by the
grants management officer is the authorizing document. Once all administrative
and programmatic issues have been resolved, the NoA will be generated via email
notification from the awarding component to the grantee business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Section
IV.5., Funding Restrictions.

We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research, peer review, and financial or grants
management issues:

Human Subjects Protection:Federal regulations (45 CFR 46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others,
and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies (Phase
I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials
(Phase III). Monitoring should be commensurate with risk. The establishment of
data and safety monitoring boards (DSMBs) is required for multi-site clinical
trials involving interventions that entail potential risks to the participants
(NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and
Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:Investigators submitting an NIH application seeking
$500,000 or more in direct costs in any single year are expected to include a
plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their
institutions, on issues related to institutional policies and local IRB rules,
as well as local, State and Federal laws and regulations, including the Privacy
Rule. Reviewers will consider the data sharing plan but will not factor the
plan into the determination of the scientific merit or the impact/priority score.

Access
to Research Data through the Freedom of Information Act:The Office of
Management and Budget (OMB) Circular A-110 has been revised to provide access
to research data through the Freedom of Information Act (FOIA) under some
circumstances. Data that are (1) first produced in a project that is supported
in whole or in part with Federal funds and (2) cited publicly and officially by
a Federal agency in support of an action that has the force and effect of law
(i.e., a regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has provided
guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Sharing of
Model Organisms:NIH is committed
to support efforts that encourage sharing of important research resources
including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh Dole Act (see the NIH
Grants Policy Statement. Beginning October 1, 2004, all investigators
submitting an NIH application or contract proposal are expected to include in
the application/proposal a description of a specific plan for sharing and
distributing unique model organism research resources generated using NIH
funding or state why such sharing is restricted or not possible. This will
permit other researchers to benefit from the resources developed with public
funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications
where the development of model organisms is anticipated.

Inclusion of Women, Minorities, and Children:It is the policy
of the NIH that women and members of minority groups and their sub-populations
must be included in all NIH-supported clinical research projects unless a clear
and compelling justification is provided indicating that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research. This policy results from the NIH Revitalization Act of 1993 (Section
492B of Public Law 103-43). All investigators proposing clinical research
should read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the SF424 (R&R) application; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of
Children as Participants in Clinical Research:The NIH
maintains a policy that children (i.e., individuals under the age of 21) must
be included in all clinical research, conducted or supported by the NIH, unless
there are scientific and ethical reasons not to include them.

Required
Education on the Protection of Human Subject Participants:NIH policy
requires education on the protection of human subject participants for all
investigators submitting NIH applications for research involving human subjects
and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

NIH Public Access Policy:NIH-funded
investigators are requested to submit to the NIH manuscript submission (NIHMS)
system (http://www.nihms.nih.gov/) at
PubMed Central (PMC) an electronic version of the author's final manuscript
upon acceptance for publication, resulting from research supported in whole or
in part with direct costs from NIH. The author's final manuscript is defined as
the final version accepted for journal publication, and includes all
modifications from the publishing peer review process.

NIH is
requesting that authors submit manuscripts resulting from 1) currently funded
NIH research projects or 2) previously supported NIH research projects if they
are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms,
cooperative agreements, contracts, Institutional and Individual Ruth L.
Kirschstein National Research Service Awards, as well as NIH intramural
research studies. The Policy applies to peer-reviewed, original research
publications that have been supported in whole or in part with direct costs
from NIH, but it does not apply to book chapters, editorials, reviews, or
conference proceedings. Publications resulting from non-NIH-supported research
projects should not be submitted.

For more
information about the Policy or the submission process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov// and view the Policy or other Resources and Tools, including the Authors' Manual.

Standards for
Privacy of Individually Identifiable Health Information:The Department
of Health and Human Services (HHS) issued final modification to the
"Standards for Privacy of Individually Identifiable Health
Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and
Accountability Act (HIPAA) of 1996 that governs the protection of individually
identifiable health information, and is administered and enforced by the HHS
Office for Civil Rights (OCR).

Decisions about
applicability and implementation of the Privacy Rule reside with the researcher
and his/her institution. The OCR website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH
Grant Applications or Appendices:
All applications and proposals for NIH funding must be
self-contained within specified page limitations. For publications listed in
the appendix and/or Progress report, internet addresses (URLs) must be
used for publicly accessible on-line journal articles.Unless
otherwise specified in this solicitation, Internet addresses (URLs)
should not be used to provide any other information necessary for the
review because reviewers are under no obligation to view the Internet sites.
Furthermore, we caution reviewers that their anonymity may be compromised when
they directly access an Internet site.

Healthy
People 2010:The Public
Health Service (PHS) is committed to achieving the health promotion and disease
prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This FOA is related to one or more of the
priority areas. Potential applicants may obtain a copy of "Healthy People
2010" at http://www.health.gov/healthypeople.

Authority and
Regulations:This program is described in the Catalog of Federal
Domestic Assistance at http://www.cfda.gov/ and is not subject to
the intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review. Awards are made under the authorization of Sections 301
and 405 of the Public Health Service Act as amended
(42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR
Parts 74 and 92. All awards are subject to the terms and conditions, cost
principles, and other considerations described in the NIH
Grants Policy Statement.

The PHS strongly
encourages all grant recipients to provide a smoke-free workplace and
discourage the use of all tobacco products. In addition, Public Law 103-227,
the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in
some cases, any portion of a facility) in which regular or routine education,
library, day care, health care, or early childhood development services are
provided to children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

Loan
Repayment Programs:NIH encourages
applications for educational loan repayment from qualified health professionals
who have made a commitment to pursue a research career involving clinical,
pediatric, contraception, infertility, and health disparities related areas.
The LRP is an important component of NIH's efforts to recruit and retain the
next generation of researchers by providing the means for developing a research
career unfettered by the burden of student loan debt. Note that an NIH grant is
not required for eligibility and concurrent career award and LRP applications
are encouraged. The periods of career award and LRP award may overlap providing
the LRP recipient with the required commitment of time and effort, as LRP
awardees must commit at least 50% of their time (at least 20 hours per week
based on a 40 hour week) for two years to the research. For further
information, please see: http://www.lrp.nih.gov/.